tbuckley/cabot-search huggingface dataset:
Abstract 1286: UNC5B promotes EMT and metastasis of pancreatic adenocarcinomas and expresses different isoforms that impact sensitivity to Netrin-1 blockade
Authors: Chris R. Harris, Orjola Prela, Lan Wang, Anthony Casabianca, Wade Narrow, Zachary Sechrist, Tracy Withers, Cory Shields, Asra Asad, Aram Hezel, Darren Carpizo
Journal: Cancer Research (2023)

Abstract The axonal guidance receptor UNC5B is considered to be a tumor suppressor because it promotes apoptosis in the absence of its protein ligand, NTN1. But we find that UNC5B is not a tumor suppressor of pancreatic ductal adenocarcinomas (PDAC), and instead promotes metastasis. In TCGA data, UNC5B expression associates with poor patient outcome. In vivo, pancreatic cancer metastasis was completely eliminated by knocking out UNC5B from the genetically engineered KPC mouse model of PDACs, and was reduced upon knockout of UNC5B in a splenectomy model of liver metastasis. An inhibitor of NTN1, NP137, also reduced metastasis in vivo. In vitro, knockout of UNC5B from mesenchymal pancreatic cell lines was sufficient to reduce many metastatic traits including invasiveness, EMT, and aerobic glycolysis. YAP1 is a known target of UNC5B and was overexpressed in high UNC5B expressing cell lines, which were sensitive to the YAP1 inhibitor CA3. NP137 is currently in clinical trial for several tumor types and we have been investigating which patients might respond best to this drug. Using an antibody (D9M7Z) that recognizes an epitope in UNC5B that overlaps with the caspase-3 cleavage site that is critical for UNC5B's apoptotic functions, we found two isoforms in murine and human PDACs: one isoform that contains the caspase-3-containing epitope as well as a previously-unreported isoform that to lack it. Cells expressing the caspase-3 site were much more sensitive to NP137. We also discovered genetic alterations in patient samples that induce expression of UNC5B. For instance, UNC5B was recurrently amplified in PDACs and these amplifications were highly focal to the UNC5B locus; also, UNC5B expression was increased by mutations of ARID1A, a component of the SWI/SNF transcription complex that is recurrently mutated in pancreatic adenocarcinomas. ARID1A mutations caused cell lines to become mesenchymal, but the cells returned to an epithelial phenotype upon knockout of UNC5B. In current and future clinical trials, NP137 may particularly benefit patients with tumors that harbor mutations in ARID1A or ARID1B, focal amplifications of UNC5B, and/or high expression of the caspase-3-containing isoform of UNC5B. Citation Format: Chris R. Harris, Orjola Prela, Lan Wang, Anthony Casabianca, Wade Narrow, Zachary Sechrist, Tracy Withers, Cory Shields, Asra Asad, Aram Hezel, Darren Carpizo. UNC5B promotes EMT and metastasis of pancreatic adenocarcinomas and expresses different isoforms that impact sensitivity to Netrin-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1286.
Abstract 1737: Genome-scale metabolic modeling reveals a metabolic switch that restores sensitivity to anticancer chemotherapy in drug-resistant breast cancer cells
Authors: JinA Lim, Hae Deok Jung, Kyung-min Lee, Moonhyeon Jeon, Han Suk Ryu, Hyun Uk Kim, Yoosik Kim
Journal: Cancer Research (2023)

Abstract Anticancer chemotherapy is an essential part of cancer treatment, but the emergence of resistance due to continued drug usage remains a major hurdle. Among the multiple mechanisms behind the acquisition of drug resistance, metabolic plasticity is receiving increasing attention. Recent proteomic and transcriptomic studies identified metabolic enzymes as potential targets for overcoming the resistance. Yet, these studies mainly focused on differentially expressed genes and overlooked the complexity of the metabolic network, especially its ability to reorganize the metabolic state in response to gene downregulation. Here, we employ the genome-scale metabolic model (GEM) to simulate the metabolic flow and identify candidates that can act as a metabolic switch for drug resistance. Using adriamycin- and paclitaxel-resistant MCF-7 breast cancer cells as model systems, we perform proteomics analysis followed by GEM construction to analyze the differential metabolic flow in the resistant cells. Moreover, we perform GEM simulations after individually knocking out every metabolic enzyme and identify a metabolic switch whose knockout restores the metabolic state of drug-sensitive MCF-7 cells. Notably, downregulating the candidate metabolic switch predicted by our model results in sensitization to the drug. We further show that the cotreatment of adriamycin or paclitaxel with a small chemical inhibitor of the metabolic switch synergistically induces cell death in drug-resistant cells. Collectively, our study demonstrates the application of GEM simulation and subsequent modulation of metabolic state as a strategy to restore drug sensitivity to overcome drug-resistant cancer. Citation Format: JinA Lim, Hae Deok Jung, Kyung-min Lee, Moonhyeon Jeon, Han Suk Ryu, Hyun Uk Kim, Yoosik Kim. Genome-scale metabolic modeling reveals a metabolic switch that restores sensitivity to anticancer chemotherapy in drug-resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1737.
Abstract 876: Sequencing a new broadly-consented tumor/normal cell line for a Genome in a Bottle Benchmark
Authors: Gail Rosen, Justin Wagner, Andrew Liss, Justin Zook
Journal: Cancer Research (2023)

Abstract Here, we describe analyses towards the first tumor/normal benchmark from the Genome in a Bottle (GIAB) consortium using new cell lines from a broadly-consented pancreatic ductal adenocarcinoma patient. This effort builds on the widely-used germline variant benchmarks for seven normal DNA reference materials. GIAB benchmarks are designed to reliably identify false positive and false negative variant calls, and are formed by combining multiple sequencing technologies and variant callers. To combine technologies and variant callers, we first understand their strengths and weaknesses for different variant types and repetitive regions. In this initial work on the new tumor/normal cell line, we have analyzed sequencing from HiC for copy number and structural variant analysis and 100to150x PCR-free Illumina WGS from normal and tumor cells for small variants. Preliminary HiC results identified substantial aneuploidy common in pancreatic tumors, with ~15 large inversions and translocations and 16 chromosomes with extensive loss of heterozygosity due to missing &amp;gt;30% of one copy. The tumor contains the common G12V mutation in KRAS, and interestingly the ~2Mbp region containing this mutation is likely triplicated. About 300 (76% of) SNVs and 10,000 (69% of) small indels agree between mutect2 and strelka2 with default filtering. After excluding difficult regions, 95% of SNVs and 94% of small indels agree, with remaining disagreements caused by systematic sequencing errors, alignment errors, low frequency, and proximity to germline variants. Examining discordant SNVs indifficult regions, most are erroneous somatic variants inregions with loss of heterozygosity that also have mapping errors due to segmental duplications, sequences missing from GRCh38, and/or tandem repeats. After excluding difficult regions, we also found that somatic SNVs fell in 4 primary classes: ~5100 in most cells in diploid regions, ~2100 in most cells in haploid regions, ~760 in only some cells in diploid regions, and ~450 in only some cells in haploid regions. GIAB plans to perform PacBioHiFi and ultra long ONT sequencing to generate phased assemblies for the normal and tumor, and is forming an open working group to develop the first authoritative benchmarks from publicly available, broadly-consented tumor-normal cell lines. Citation Format: Gail Rosen, Justin Wagner, Andrew Liss, Justin Zook. Sequencing a new broadly-consented tumor/normal cell line for a Genome in a Bottle Benchmark [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 876.
Abstract 1420: The non-canonical role of Rb in enhancers and insulators
Authors: Hanjun Lee, Ioanna M. Gkotinakou, Ioannis Sanidas, Michael S. Lawrence, Nicholas J. Dyson
Journal: Cancer Research (2023)

Abstract Despite the great significance of the tumor suppressor Rb in cancer biology, the full spectrum of its binding pattern in human cells was yet to be established. Here, we report that rather than exclusively associating with E2F-bound promoters, chromatin-bound Rb associates with three distinct types of loci—E2F1-bound promoters, AP-1-bound enhancers, and CTCF-bound insulators. The binding pattern of Rb correlated with cohesin binding and chromatin accessibility in all three types of Rb-bound regions. When cells entered the S phase after the G1/S checkpoint, Rb redistributed from promoters to enhancers, leading to distinct transcriptional changes. These Rb-bound enhancers were cell-type-specific, in contrast to Rb-bound promoters that were constitutively present throughout most human cell types. Overall, our study provides a comprehensive view on the role of the tumor suppressor Rb, which has a well-preserved role in the G1 phase of regulating transcription at E2F1-bound promoters, while having a cell-type-specific role in the S phase when cells are determined to replicate. Citation Format: Hanjun Lee, Ioanna M. Gkotinakou, Ioannis Sanidas, Michael S. Lawrence, Nicholas J. Dyson. The non-canonical role of Rb in enhancers and insulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1420.
Abstract 792: SARS-CoV-2 spike S1 mediated lung tumor regression in a mouse model
Authors: Monica Sheinin, Kalipada Pahan, Ramesh K. Paidi
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer related deaths worldwide, with a relatively low 5-year survival rate. Although there are some therapies against lung cancer, new effective treatment options are urgently required. Recently during the COVID-19 pandemic, we have seen that SARS-CoV-2 binds to its receptor angiotensin-converting enzyme 2 (ACE2) via spike S1 to enter the cells. This study underlines the importance of SARS-CoV-2 spike S1 in inducing death in human lung cancer cells. Interestingly, we have seen that recombinant spike S1 treatment at very low doses led to death of human A549 lung cancer cells. On the other hand, boiled recombinant SARS-CoV-2 spike S1 remained unable to induce death, suggesting that the induction of cell death in A549 cells was due to native SARS-CoV-2 spike S1 protein. SARS-CoV-2 spike S1-induced A549 cell death was also inhibited by neutralizing antibodies against spike S1 and ACE2. Moreover, our newly designed wild type ACE2-interacting domain of SARS-CoV-2 (wtAIDS), but not mAIDS, peptide also attenuated SARS-CoV-2 spike S1-induced cell death, suggesting that SARS-CoV-2 spike S1-induced death in lung cancer cells depends on its interaction with ACE2 receptor. Similarly, recombinant spike S1 treatment also led to death of H1299 and H358 human lung cancer cells. Finally, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) intoxication led to the formation tumors in lungs of A/J mice and alternate day intranasal treatment with low dose of recombinant SARS-CoV-2 spike S1 from 22-weeks of NNK insult (late stage) led to induced apoptosis and tumor regression in the lungs. These studies indicate that recombinant SARS-CoV-2 Spike S1 protein may have implications in the treatment of lung cancer. Citation Format: Monica Sheinin, Kalipada Pahan, Ramesh K. Paidi. SARS-CoV-2 spike S1 mediated lung tumor regression in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 792.
Abstract 854: A pharmaco-pheno-multiomic integration analysis of pancreatic cancer: A highly predictive biomarker model of biomarkers of Gemcitabine/Abraxane sensitivity and resistance
Authors: Gilad Silberberg, Clare Killick-Cole, Yaron Mosesson, Haia Khoury, Xuan Ren, Mara Gilardi, Daniel Ciznadija, Paolo Schiavini, Marianna Zipeto, Michael Ritchie
Journal: Cancer Research (2023)

Abstract The overall survival of patients diagnosed with Pancreatic Cancer remains low. Initial responses to current therapeutic interventions are below 50%, leading to a high mortality rate shortly after diagnosis. To date, only a companion diagnostic, non-specific for pancreatic cancer, has been approved for this indication. A better understanding of the tumor cell biology and resistance mechanisms may shed light onto novel therapeutic targets that improve long-term outcome and improved patient stratification. In this study, we performed an exhaustive analysis to identify predictive biomarkers for gemcitabine/abraxane sensitivity using multiomics datasets. These datasets were integrated in a pharmaco-phenotypic-multiomic (PPMO) model predictive of therapeutic sensitivity or resistance, using sparse partial least squares (sPLS). Our results reveal major cellular discriminants in genomic variants, transcriptomics, and most pronouncedly in proteomics data. Tumors exhibiting Gemcitabine/Abraxane resistance associate with increased TPRV6 RNA expression, MUC13 protein expression, and USP42 mutation among others. Prospective application of the PPMO integration model was able to accurately predict Gemcitabine/Abraxane response profiles for 4/5 additional Pancreatic samples, therefore suggesting a potential application as a predictive diagnostic tool. Citation Format: Gilad Silberberg, Clare Killick-Cole, Yaron Mosesson, Haia Khoury, Xuan Ren, Mara Gilardi, Daniel Ciznadija, Paolo Schiavini, Marianna Zipeto, Michael Ritchie. A pharmaco-pheno-multiomic integration analysis of pancreatic cancer: A highly predictive biomarker model of biomarkers of Gemcitabine/Abraxane sensitivity and resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 854.
Abstract 1422: Fibroblast growth factor receptor-1 is a novel therapeutic target in mantle cell Lymphoma
Authors: Anuvrat Sircar, Satishkumar Singh, Ken H. Young, Narendranath Epperla, Lalit Sehgal
Journal: Cancer Research (2023)

Abstract Cell cycle dysregulation and significant enrichment of E2F1 target genes are hallmarks of MCL, and the inability to directly target E2F1-dependent processes is a clinical hindrance. Despite several treatment options, mantle cell lymphoma is associated with poor clinical outcomes and the development of resistance. We identified Fibroblast Growth Factor Receptor-1 is upregulated in relapsed mantle cell lymphoma patients and high FGFR-1 expression in MCL correlates with poor overall and progression-free survival. Genetic ablation of FGFR1 in MCL cells induced cell cycle arrest, and cell death in-vitro, inhibited tumor progression, and improved overall survival in-vivo. Functionally, FGFR1 loss upregulates the expression of the cell-cycle dependent Kinase inhibitor 1C (CDKN1C) through epigenetic repression via EZH2. CDKN1C binds to E2F1 and regulates the transactivation of its target genes, including CDK1. CDK1 further stabilizes MYC and positively regulates the expression of EZH2, activating the feed-forward loop to promote cell survival. Conversely, losing FGFR1 disrupts this feed-forward loop in malignant cells. This is the first report establishing FGFR1 as a novel therapeutic target and providing a rationale to target FGFR1 to treat Mantle cell lymphoma and disrupt the feed-forward loops contributing to the survival of malignant cells. Citation Format: Anuvrat Sircar, Satishkumar Singh, Ken H. Young, Narendranath Epperla, Lalit Sehgal. Fibroblast growth factor receptor-1 is a novel therapeutic target in mantle cell Lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1422.
Abstract 1572: Antiproliferative activity of enzalutamide and alisertib in prostate cancer cells overexpressing HMGA2
Authors: Yusuf Mansur Liadi, Valerie Odero-Marah
Journal: Cancer Research (2023)

Abstract Prostate cancer is one of the common types of cancer and remains the second leading cause of cancer-related deaths in men in the United States. High Mobility Group Protein AT-hook 2 (HMGA2), a DNA binding protein acts as a transcriptional regulating factor in gene transcription and facilitates epithelial-mesenchymal transition (EMT), which is usually the onset of prostate cancer progression and metastasis. HMGA2 isoforms include wild-type or full length that induces EMT, while the truncated isoform is associated with elevated proliferation and migration. Enzalutamide is a second-generation antiandrogen drug known to inhibit androgen receptor (AR) translocation into the nucleus by competitively binding AR and preventing androgen binding. Alisertib (MLN8237) is a small molecule inhibitor of Aurora kinase A has been utilized in clinical trials for neuroendocrine cancers and can also inhibit EMT. We aim to investigate which of the two drugs is effective in reducing proliferation in prostate cells overexpressing HMGA2 isoforms (wild-type and truncated). In this study, we treated LNCaP cells overexpressing HMGA2 with enzalutamide (1-30 µM) and alisertib (2.5-40 µM). Treatment with enzalutamide and alisertib indicated a dose-dependent decrease in cell proliferation with optimal dose at 20 µM for both drugs. LNCaP cells (LNCaP Neo) expressing low level of HMGA2 were observed to respond better to enzalutamide treatment, while those overexpressing HMGA2 (WT and TR) respond better to alisertib treatment. Interestingly, treatment with 20 µM enzalutamide and alisertib followed by Western blot indicated enzalutamide to have no effects on protein expression of HMGA2 isoforms, but greatly decreased the expression of AR in LNCaP cell overexpressing truncated HMGA2. On the other hand, alisertib increased the expression of wild-type HMGA2 whilst having no effects on protein expression of AR. Both drugs at 20 µM did not have any significant effect on the expression of EMT markers (snail and vimentin).In conclusion, alisertib is more potent than enzalutamide in decreasing cell proliferation in prostate cancer cells expressing HMGA2. Further studies need to be conducted to understand the role of HMGA2 in promoting resistance to enzalutamide and whether alisertib may be a better drug for patients that express HMGA2. Acknowledgements: These studies were supported by NIH/NIMHD 2U54MD007590 and 5U54MD013376-8281. Citation Format: Yusuf Mansur Liadi, Valerie Odero-Marah. Antiproliferative activity of enzalutamide and alisertib in prostate cancer cells overexpressing HMGA2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1572.
Abstract 3685: Targeting a novel cell surface serine protease TMPRSS11B for lung cancer therapy
Authors: Hari Shankar Sunil, Barrett Updegraff, Jingfei Zhu, Bret M. Evers, John D. Minna, Ralph J. Deberardinis, Trudy G. Oliver, Kathryn A. O'Donnell
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Patients have few therapeutic options, and disease progression is inevitable. Anti-PD-1/PD-L1 antibodies can induce potent anti-tumor immunity and have been approved as a first-line therapy for non-small cell lung cancer (NSCLC). However, only ~20% of all NSCLCs benefit from checkpoint blockade, underscoring the critical need for the development of new and innovative approaches to identify actionable therapeutic targets to treat NSCLC. We identified the Transmembrane Serine Protease TMPRSS11B as a novel gene that promotes the transformation of human bronchial epithelial cells in vitro and induces tumorigenesis in vivo (Updegraff et al., Cell Reports, 2018). Our data show that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporters MCT1 and MCT4, and that TMPRSS11B interacts and co-localizes with Basigin and MCT4. Moreover, Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. This is of significant interest because TMPRSS11B is frequently overexpressed in human lung squamous cell cancers (LSCC) and high expression is associated with poor survival of NSCLC patients. Moreover, as a cell surface protein and enzyme, TMPRSS11B represents an exciting putative target for therapeutic intervention. Our new studies demonstrate that the catalytic activity of TMPRSS11B may be important for the interaction with Basigin and enhanced lactate export. We also evaluated the effect of Tmprss11b depletion in the KLN205 syngeneic LSCC mouse model. CRISPR/Cas9 knockout of Tmprss11b in KLN205 LSCC cells significantly reduced tumor burden in immunocompetent DBA/2 WT mice. Moreover, mass spectrometry analysis revealed TMPRSS11B-interacting proteins that may represent novel substrates of this enzyme. Current studies are focused on elucidating the molecular mechanisms through which TMPRSS11B promotes tumorigenesis and investigating the efficacy of TMPRSS11B inhibition in syngeneic and autochthonous mouse models of LSCC, where the effects on immune cell function will be assessed. Citation Format: Hari Shankar Sunil, Barrett Updegraff, Jingfei Zhu, Bret M. Evers, John D. Minna, Ralph J. Deberardinis, Trudy G. Oliver, Kathryn A. O'Donnell. Targeting a novel cell surface serine protease TMPRSS11B for lung cancer therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3685.